7-hydroxy coumarin deriv atives



Original Filed July 26, 1962 INVENTOR. HE\NP-\CH PATTY-1R RU D\ BEY E'RLE BY ROLF EBRHARD NlTZ.

FRANCIS M. CRAWFORD United States Patent C) 9 Claims. (Cl. 260--343.2)

This application is a division of parent application Ser. No. 212,657, filed July 26, 1962, and is entitled to the same priority dates claimed in said parent application.

The administration of coronary vasodilators is to bring about an enhanced blood flow in the coronary vessels. The conventional coronary vasodilators, however, involve the disadvantage of exercising merely a non-specific vasodilator action on the coronary vessels because they simultaneously cause a dilatation of other large blood vessel, areas, which is symptomatic of a considerable decrease in blood pressure. This hypotension does not allow the use of the known coronary vasodilators in hypotonic patients and in those having an acute myocardial infarction. In such cases the known agents may even evoke a paradoxical eiect on the coronary vessels, namely a coronary blood ow decreasing effect (see Scheler and Bretschneider, Verhandlungen der deutschen Gesellschaft fr Kreislauiiorschung, vol. 26, page 254 (1960)). Moreover, the known coronary vasodilators have only a relatively short-term action. Consequently, the objective of our interest has been directed to the development of such coronary vasodilators as specifically dilate the coronary vessels only and, thus, do not exhibit a hypotensive action and which especially possess a longterm activity.

Now, we have found that the desired properties inhere in the derivatives of the 7-hydroxy-coumarins of the general formula wherein R1 is a substituent of the group consisting of a hydrogen atom, an alkyl, alkenyl, aryl-, aralkyl, heteroalkyl, aminoalkyland a carbalkoxyalkyl radical, R2 is a substituent of the group consisting of an alkyland aryl residue, R3 is a substituent of the group consisting of an alkenyl, carbalkoxyalkyl, carboxyalkyl, carbamidoalkyl radical and, if R1 is an aminoalkyl radical, furthermore an alkyl radical and R4 is a substituent of the group consisting of a hydrogen atom and the residue -OR3.

The new 7-hydroXy-coumarin derivatives are obtained in the known methods by allowing 7-hydroxy-cournarins of the general formula wherein R4 is a hydrogen atom of a hydroxyl group, to react with halogen compounds of the formula RaHal, in the presence of an acid-binding agent, or by condensing ice with cyclization substituted hydroxy-cinnamic acids of the general formula l llz 1,11

C=CCOOH RQO- OH or their functional derivatives or by condensing oxybenzenes of the general formula with -keto-acid esters of the general formula i i RPO-CH-Co oalkyi or, if R3 has the meaning of a carbamido-alkyl radical, by aminating 7-hydroxy-coumarin derivatives of the general formula Ra Iliz aikyi-coo-alkyiene-O- \O/*O with ammonia or primary or secondary amines.

The 7-hydroxy-coumarins being required, interalia, as starting products may be obtained according to known methods, by condensing in the presence of an acid condensation agent -keto-acid esters of the general formula az--ontRo-o o oaikyl being correspondingly substituted with hydroxybenzenes of the general formula HO- OH Following the pharmacological tests in laboratories, which are described hereinafter the most active derivatives of the 7hydroxycoumarines had been subjected to clinical experimentation, the results of which will also be stated hereinafter.

The pharmacological investigation of the substances according to our present invention with respect to their coronary vasodilator action was carried out in dogs according to the method disclosed by Eckenhoii, Hafkenschiel and Landmesser (Am. J. Physiol. 148, 582 (1947)). The test preparations were applied intravenously to the animals narcotized. The coronary blood flow was measured by means of an automatic Bubble-Flow-Meter and the blood pressure was measured in the femoral artery by means of Van Anderson-Glass-Capsule Manometer. During the test period the animals were given articial respiration. On these test conditions the dilatation of the coronary artery being caused by the test substance, gives rise to a more rapid bubble flow, whereas a constriction of the coronary vessels becomes evident from a retardation of the bubble ow, which is recorded by a kymograph. In all these tests there was used papaverine as a comparative standard substance.

FIGURES 1 and 2 illustrate graphically the results obtained when using different amounts of papaverine in comparison to 3--diethylaminoethyl-4-methylcournarin- 7-ethyl oxyacetate chlorhydrate.

a ,Wifhineeh figure Curve II represents the action of 0.8 mg./kg. papaverine, Curve III represents the action of 0.8 Vmg./ kg. S--diethyl- For clinical investigation there has been used especially acetate chlorhydrate. In various clinics the preparation was addinistered both in the form of dragees and in the aminoethyl 4 methyl coumarin 7-ethy1 oxyacetate 5 for@ o? solutions 'for mitral/61101.45 and. iiltramuscular in' chorhydra jection in the case of ino'st diversified clinical appearances. Curve IV replfesents the action of 1.265 Ing/kg. 3 The dragees were administered in adosage of 15-50 m1111- diethylaminoethy1 4 methy1 coumarin 7 ethy1 0Xya grams three times daily and the.intravenoussolution was tate chlorhydrate, given in a dosage of 10-20 milligrams once daily. In Curve V represents the action of 2 Ing/kg 3 diethy1 10 none of the cases, side-effects of the substance had been aminoethyl-l-methyl-coumarin-7-ethyl oxyacetate chlorobsewfi- Thi@ followmg dlagnoses had been made m hydrate the patients singled out for these tests: hypercholesterinemia coronary sclerosis, myocardial infarction, steno- FIGURE 1 indicates the influence of the substance upon ma the coronary flow and FIGURE 2 the influence upon the 15 cardla. cardlsclerosls cqronary msumclency and ang blood pressure. The data forming basis of the diagram peqtone' 'grav1,s' ,In 'praFucauy au of, the Cases under eX' represent the mean value of the results of measurement ammatmn Slgmcant lmprovemerft m the state of health ascertained in tests on 8 animals each. The administraof the Pane/nfs WS Observed Winch led to a complete tion of doses higher than 0.8 mg./l g. papaverine is imfedfess f then Da lns and COIHPHIDS- possible because otherwise a too sharp decrease in blood 1.11 ih e PfeRafalOn 0f dragees and tablets COIlallfllUg as pressure occurs. The iigures show the clear superiority GUYS lngljedlent -he 7'hYdT0XYC0umaY11'1 .deflvaflves Pf of the hydroxy-coumarin derivative under our invention 0U1`1I'1Ye11011-, these Substances may be ad'mlXed Wlfh Sohd over the standard substance papaverine which, on the one tfflbletlng adlUVaDS, vSUC h 3S Stafqh, 13H05?, talc and the hand lies in the degree of the influence upon the coronary 1114 ADY 0f the ableftlrlg materlls Used 1n pharmaceuow and 'on the other hand, in the duration of this in- 25 tical practice may be employed. For the preparation of fluence (see FIGURE l) and, furthermore, they show the injection solutions there are particularly suited the the difference in the change of blood pressure (see FIG- derivatives of the 7-hydroXy-courmarins being basically URE 2). substituted since they are water-soluble in the form of On the same test conditions some further substances of their salts. Injection solutions of water-insoluble products our invention had pharmacologically been tested and the may of course be prepared in the conventional manner mean values of the test results obtained areindicated in by concurrently using well-known suspending agents, the following table. emulsiiiers'and/or solubilizers.

i Dosage Maximum Duration of Changein Substance LDg./kg. mgJkg., increasein actionin blood presmouse, .v. i.v. the coronary minutes sure, percent flow', percent Papaverine 0.033 0.8 24 8 -20 B--diethylaminoethyl-i-methylcouma- 0. 8 22 60 +2 rin-7-ethy1oxyacetate chlorhydrate 0. 034 (2)65 60 +2 5 -4 3--pyrroidinoethyM-rnethylcoumarin- 7 7etliyl oxyacetatechlorhydrate 0. 04 1. 0 63 26 :|10 3piperidinoethylA-methylcouinarin- 0. 2 26 19 +2. 2 7-ethyl oxyacetate chl0r1iydrate g- 0. 016 0. 4 37 28 0. 5

1.0 74 50 io B--morpholinoethyl-et-methyl-couxnarm- 7-ethy1 oxyacetate chlorhydrate 0. 11 1. 0 21 16 i() 3--piperidinoetliyl-4-methyl-7-allyloxycoumarin chlorhydrate 0. 048 1. 0 94 30 +11, 3 3--diethy1aniinoethyl-i-phenylcoumarinmethyl-coumarin-7-ethyl-oxyacetate chlorhydrate 0. 058 0. 8 43 65 3--diethylaininoethyl-i-inethyl-coumarin-7-oxyacetic acid am.inoethyl amide 2.0 130 40 l 15% untill() minutes after the injection, later 10%.

Furthermore, comparative tests had been made on the same conditions as described before, however, with intracoronary administrationV ofthe following substances and papaverine in equal dosages.

-l-:having the same action as papaverine,` and ++=having an action intenser and longer than papaverine.

, LDsog./ kg Substance mouse, Lp. Activity Papavprine 3-butyl-4-methy1-coumarin-7-etliyl oxyacetate.

3-phenyl-4-metliy1coumarin-7-isopropy1 oxyacetate The following examples are given for the purpose of characterizing the substances of the present invention. All temperatures given are in degrees centigrade.

Example 1 added. It is heated until boiling and stirred for 8 hours at the boil. The reaction mixture is filtered off with suction in the heat and the filtrate is concentrated in the vacuum to dryness. The residue is dissolved in methylene chloride,V washed several times fwith diluted sodium hydroxide solution and the solution of methylene chloride is evaporated to dryness. The raw product may be re crystallized -from ethyl acetate for further purication. White needles having a melting point of 137138 are obtained,

Yield: 14 grams 4-phenyl-coumarin7ethyl oxyacetate solved in 120 ccm. methylethyl ketone and admixed with l2 grams anhydrous poatssium carbonate. This mixture is stirred for 1 hour at 70 and then 11 grams bromoacetic acid ethyl ester are allowed to drop in. Then the 5 mixture is stirred under reilux for another 9 hours. (`71`8% of the theory) According to the recipe indicated in Example 1, 3-allyl-4- Example 2 methyl-coumarin-7-ethyl oxyacetate having a melting 18 grams 3-butyl-4-methyl-'7-hydroxy-coumarin (pre- Pomt of 42440 1S Obtamed m a good yield' pared by condensation of a-butylacetic acid ethyl ester Example 6 with resorcin acording to the method s eciiied in Org. 10 Synth. vol. 21, page 23) are suspended inp200 ccm. meth- 18'7 .grams 3''dlethylaminthyl'i'methyl'l'hydroxy' ylethyl ketone. 12 grams anhydrous Potassium carbom coumarrn chlorhydrate are dissolved 1n 200. ccm. methylate are added and the mixture is stirred for 1 hour at 70. ethyltgne d 18. grams. anhydrgl; potslum Cargnat Then 0.5 gnam potassium iodide is introduced into the age 31260 mlxture .1S stlire hir l our 31H7 an reaction -mixture and 16 grams ibromoacetic acid ethyl 15 gen crfls r0m.Oacetl.Ctac1 .et Y eser ae a (wedfto ester are allowed to drop in. The mixture is heated until 91's m d teheaupnggx rfls Sireu En e? rl will otr boiling and stirred for 8 hours at the boil Then the The ltliir: is ccr 1nizeiistrate 1iein thevacusurrsilc;1 ees ggd reaction mixture is filtered oi with suction in the heat the resultant residue is dissolved in ether .Uilen esthe: and worked up as indicated in Example 1. The raw l t. h d .th d.1 t d t. l t. f1 product may be recrystallized from ethyl acetate for furso u 10111.15 was s l u e gaps 1c .so also ,m or ther purication. The 3-butyl-4-methyl-coumarin-7-ethyl severa times. su sequently rld Wlth. G au er s Saly y introduction of hydrochlorlc acld gas into the etherlc oxyacetate thus obtained forms white needles havmg a 1 t. th t. d t. .t t d. h f melting point of 78- pllrxrlldraetzereac ion pro uc 1s preclpi a e 1n t e orm o Yleld' 20 grams=83`5% of the theory' 25 Yield: 15 grams 3--diethylaminoethyl-4-methyl-cou- Example 3 marin-7-ethyl oxyacetate chlorhydrate having a melt- 17.6 grams 4-methyl-7-hydroxy-coumarin (prepared by mg pomt of 1544560 (:63% of the theorw' the method indicated in Org. Synth. vol. 2l, page 23) According to the process described in this example there are dissolved in 180 ccm. methylethyl ketone and, whilst 30 may be prepared in an analogous manner the following adding 16 grams anhydrous potassium carbonate, they compounds of the general formula are allowed to react with 18.5 grams bromoacetic acid ethyl ester according to Example l. Thus, 4-rnethyl- If coumarin-7-ethyl-oxyacetate having a melting point of R 98100 are obtained. 35 l Yield: 19 grams=72.5% of the theory. Rao- \O/ 0 Example 4 2O grams 3-phenyl-4-methyl-7-hydroxy-coumarin (pre- Mening pared by condensation of resorcin with a-phenyl-aceto- R1 R R3 tllllgi acetic acid ethyl ester as indicated in J. Chem. Soc. 109, hydrates 110 and I. Chem. Soc. 127, 1983) are suspended in 200 ccm. methylethyl ketone and admixed with 20 grams an- -diethylaminoethyl Methyli-.. Ethy1 22o-222 hydrous potassium carbonate. The mixture is stirred for 32:11:21:" jggj: g': gjg: one hour at 70 and then 15 grams chloroacetic acid tert. 45 -piperidinoethylm-- do Allyl 220-222 butyl ester are allowed to drop in. Subsequently, it is 'dlethylammoethyl Pheny Ethyl 15s-160 heated until boiling and stirred for another 9 hours at the o boil. Now the reaction mixture is filtered off with sucgjgllgfglgtetl: gjggu tion in the heat and the filtrate is concentrated in the -pyrroliduoethvl 1232-183; vacuum. The residue is dissolved in methylene chloride, iff)gifggfggogf51i lwg@ the solution is washed for several times with diluted sodium h droxide solution land, subsequentl the methylene chlxdride solution is concentrated in the vacuum to 3''dlethylammOethyl'ii'nflethyt'cmimarmq'ethyl Oxy' dryness. The remaining ray product is recrystallized acetat chlorhydrate desnbfd m thls example can pe from benzine' 55 saponlt'ied to the free acld 1n a known method by d1ssolving 4 grams of the chlorhydrate in 40 ccm. water and Yleld: 20 grams 'phenyl'A'methyl'coumarmqfert butyl heating this solution for 4 hours under retlux. When suboxyatate havmg a' meltmg pomt of 11S-1 15 (=69 sequently concentrating the aqueous solution in the vacu- Of the'theorw' um to dryness, a white crystalline residue is obtained In an analogous manner, there may be prepared the which represents the 3--diethylaminoethyl-4-methyl-coufollowing 7-oxy-coumarin derivatives: marin-7-oxyacetic acid chlorhydrate having a melting Starting materials Final product lgiecgiit 3-phenyl-4-rnethyl-7- Chloroaeetie acid-iso- S-phenyl-t-methyl-cou- 13S-140 70 hydroxy-coumarin. propyl ester. marin-7-isopropyl oxy- 3-ethyl-4-phenyl-7- Chloroacetic acid-tert. S-clyllle-phenyleoumarin 122-123 64 hydroxy-coumarin. butyl ester. 7-tert. butyl oxyacetate.

Do Chloroacetic acid-isopropyl 3-ethyl-4-pheny1-coumarin- 124-125 77 ester. 7-isopropyl oxyacetate. 3-benzyl-4-methyl7 Bromoaeetic acid-ethyl 3benzyl4methylcou 117-120 66 hydroxy-coumariu. ester. marin-7-ethyl oxyacetate.

Example 5 point of 70-75.

12 grams 3-allyl-4-methyl-7-hydroxy-coumarin are dis- 75 tative.

The yield of the saponification is quanti- Example7 14 grams 3-carbethoxyrnethyl-Lt-methyl-5,7dihydroxylcoumarin (prepa-red by condensation of phloroglucine with acetylsuccinic acid diethyl ester according to the method indicated in Chemical Abstracts vol. 37, 14302 (1943)) are suspended in 200 ccm. methylethyl ketone and 20 grams anhydrous potassium carbonate are added. This mixture'is stirred for 1 hour at 70 and then 20 grams bromoacetic acid ethyl ester are allowed to d-rop Lin. Then the mixture is heated until boiling and stirred for 9 hours at the boil.

Yield: 13 grams 3-carbethoxymethyl-4-methyl-coumarin- 5.7di(ethyl oxyacetate) having a melting point of 11G-112 (=57.5% ofthe theory).

Example 8 10 grams 3--diethylaminoethyl-4-methyl-coumarin-7- ethyl oxyacetate chlorhydrate are stirred together with 75 grams ethylene diamine for about 15 hours at 20-25. The resultant colorless precipitate is ltered oif with suction, washed with water and dried. Thus, 8 grams 3-,8-diethylaminoethyl-4-methyl-couniarin-7-oxyacetic acid aminoethylamide are obtained which, after recrystallization from water, are colorless crystals having a melting point of 118-119".

When using concentrated ammonia instead of ethylene diamine, there is obtained in an analogous manner the 3 diethylaminoethyl-4-methyl-coumarin-7-oxyacetic acid amide in the formof colorless crystals having a melting point of 186-187 When using in this example instead of ethylene diamine, one of the following amines, the corresponding lamides of the 3--diethylaminoethyl-4-rnethyl-coumarin- 7-oxyacetic acid are obtained:

18.7 grams 3--diethylaminoethyl-4-methyl-7-hydroxycoumarin-chlorhydrate are suspended in 280' ccm. methylethyl ketone and, after the addition of 20 grams ani hydrous potassium carbonate, the mixture is stirred for 4 hours at 70. Subsequently, a solution consisting of 9 grams N,Ndimethyl-chloroacetamide in 25 ccm. methylethyl ketone is allowed to drop into the reaction mixture and is stirred for 8 hours at 70 After cooling, the solution is filtered off with suction and the iiltrate is concentrated in the vacuum to dryness; the residue is dissolved in ethyl acetate and washed for several times with diluted sodium hydroxide solution.V

The ethyl acetate layer is eliminated and dried. Hydrochloric acid gas is introduced vinto this solution for precipitating the chlorhydrate of ythe iinal product. Thus,

8 3 `diethylaminoethyl-4-methyl-cou1narin-7-oxyacetic acid dimethylamide chlorhydrate is obtained having a melting point of 203-206".

Yield: 14 grams-:59% ofthe theory.

In an analogous manner, there is obtained Ithe 3--diethylaminoethyl 4 methyl-coumarin-7-oxyacetic acid dibutylamide chlorhydrate having a melting point of 129- Y130" by allowing 3--dethylaminoethyl-4-rnethyl-7-hydroxy-coumarin-chlorhydrate to react with N,Ndibutyl chloroacetamide.

It will be understood that this invention is susceptible to further modification and, accordingly, it is desired to vcomprehend such modifications within this invention as may fall within the scope of the appended claims.

We claim:

1. A compound of the formula wherein R1 is selected from the group consisting of lower alkyl, phenyl, benzyl and allyl; R2 is selected from the group consisting of lower alkyl and phenyl, and R3 is an alkyl radical having 2-4 inclusive carbon atoms.

2. 4-phenyl-coumarin-7-ethyl oxyacetate having the formula HaCzOOC-CHz-O- \O O 4. 3-phenyl-4-methyl-coumarin-7-tert. butyl oxyacetate having the formula 6. 3-ethyl-4-phenyl-coumarin-7-tert.

butyl oxyacetate having the formula 9 10 7. 3-ethy1-4-pheny1-coumarin-7 -isopropyl oxyacetate 9. 3-a1ly1-4-methy1-cournarin-7-ethy1 oxyacetate having having the formula the formula CIJHn (11H,

02H5 5 Cin-Gudula, H3C\ EC-OOC-CHFO- \O/ 0 HCzOoC-CHi-O- \O 0 H3C 8. 3-benzy1-4-methyl-coumarin-7-ethy1 Oxyacetate hav- 10 References Cied in the me 0f this Patent ing the formula UNITED STATES PATENTS (|351 2,680,746 6/1954 Schapp 260-3432 01H1 WALTER A. MODANCE, Primary Examiner.

15 JOHN D. RANDOLPH, I. A. PATTEN,

H5020 0 C`C Hz-O- \O/0 Assistant Examiners. 

1. A COMPOUND OF THE FORMULA 2-(O=),3-R1,4-R2,7-(R3-OOC-CH2-O-)-2H-CHROMENE WHEREIN R1 IS SELECTED FROM THE GROUP CONSISTING OF LOWER ALKYL, PHENYL, BENZYL AND ALLY; R2 IS SELECTED FROM THE GROUP CONSISTING OF LOWER ALKYL AND PHENYL, AND R3 IS AN ALKYL RADICAL HAVING 2-4 INCLUSIVE CARBON ATOMS. 